The objective of this proposal is to define the role of certain newly identified peptides in the lung as mediators of pulmonary vascular and airway responses. These peptides, acting mainly as neurotransmitters, are normally present or released in the lung, have potent biological actions, and are capable of producing such responses as pulmonary vasoconstriction or vasodilation, airway constriction or relaxation, pulmonary edema and systemic hypotension. Our specific goals are to: 1) isolate to homogeneity and characterize two novel vasoactive peptides from the lung: VIP and "spasmogenic lung peptide"; 2) determine the full biological activities of these peptides on pulmonary vessels and airways; 3) examine their release in experimental models of specific pulmonary vascular and airway responses; and 4) evaluate the role of VIP as the transmitter of the non-adrenergic, non-cholinergic relaxant system in airways and pulmonary vessels. Methods will include biochemical, physiologic and pharmacologic techinques. Experiments will be performed on anesthetized dogs, unanesthetized sheep, isolated perfused lungs, and lung tissue in vitro. Data will be based on bioassays and radioimmunoassays, and measurements of pulmonary vascular pressures, blood flow, pulmonary lymph flow and protein content, as indicators of pulmonary hemodynamics and microvascular permeability. The proposed project is a continuation of research that has already led to the discovery, identification and partial characterization of two biologically active peptides present in normal lung, as well as the complete isolation of VIP from intestine and other tissues. The research represents a coordinated attack on some fundamental questions relating to major diseases of the pulmonary circulation and airways.